Diagnostic Approach to Myeloproliferative Neoplasms

2008 WHO Classification Scheme for Myeloid Neoplasms

Polycythemia VeraEssential ThrombocythemiaPrimary Myelofibrosis

Chronic Neutrophilic LeukemiaChronic Eosinophilic Leukemia, NOSHypereosinophilic SyndromeMast Cell DiseaseMPNs, unclassifiable

Chronic Myelomonocytic LeukemiaAtypical Chronic Myeloid LeukemiaJuvenile Myelomonocytic LeukemiaMDS/MPN, unclassifiable

Chronic Myelogenous Leukemia

Myeloid neoplasms associated with PDGFRA rearrangementMyeloid neoplasms associated with PDGFRB rearrangementMyeloid neoplasms associated with FGFR1 rearrangement (EMS)

Acute

Chronic

Acute Myeloid Leukemia

Myelodysplastic Syndromes

Myeloproliferative Neoplasms

MDS/MPN

Myeloproliferative neoplasms associated with eosinophilia and

abnormalities of PDGFRA, PDGFRB, or FGFR1

• A 55 year-old man presents for routine evaluation

• CBC reveals erythrocytosis with mild leukocytosis and thrombocytosis:

What is your differential diagnosis?

• Relative erythrocytosis

– Secondary to decreased plasma volume

– Hemoglobin > 18.5 gm/dL (males) or > 16.5 gm/dL (females) diagnostic for absolute erythrocytosis

– Otherwise, measure RBC mass

• Absolute erythrocytosis

– Polycythemia vera

– Secondary erythrocytosis

Differential diagnosis of erythrocytosis

Polycythemia vera – clinical features• May be incidental finding of high Hgb/HCT

• Non-specific complaints: HA, weakness, dizziness, excessive sweating

• Pruritus

– Typically after hot bath/shower or rubbing of skin

– Presumed 2/2 mast cell degranulation – histamine, prostaglandins, etc...(unproven)

– Consistent with finding that ASA can relieve pruritus in some patients

• Erythromelalgia/acral paresthesias

– Burning pain/parasthesias in hands/feet accompanied by erythema, pallor, or cyanosis

– Thought to be 2/2 microthrombi; associated with thrombocytosis

– Responds dramatically to ASA or reduction of plt count to normal

Polycythemia vera – clinical features

• Thrombosis (venous or arterial)

– Risk factors include age, h/o prior thrombosis, leukocytosis

• Extreme thrombocytosis and CV risk factors may also be risk factors (controversial)

– Suspect PV in patients with unusual sites of thrombosis, e.g. Budd-Chiari, portal, splenic, or mesenteric vein thrombosis, particularly in women < 45

– Transient visual disturbances (e.g. amaurosis fugax, migraine)

• Splenomegaly +/- hepatomegaly

Diagnostic approach to erythrocytosis

Polycythemia Vera Diagnostic Criteria

Polycythemia Vera Course and Prognosis

• Median survival is ~ 14 years

• Chronic phase may last for years

• Progression to: – Myelofibrosis (~10% at 10 years)

– AML (1-5% at 10 years)

• Thrombosis major source of morbidity and mortality

Polycythemia Vera Treatment

• Low dose aspirin indicated for all patients

• Phlebotomy: Goal to Hct < 45 (< 42 in females)

• Myelosuppression (usually hydroxyurea)

– Typically used in patients at high risk for thrombosis (age > 60 or prior h/o thrombosis)

• Alpha-interferon (younger high-risk patients)

• A 66 year-old woman presents with headaches and recurrent TIA symptoms

• CBC reveals thrombocytosis:

Differential Diagnosis of Thrombocytosis

• Reactive (secondary) thrombocytosis

– Infection/inflammation

– Iron deficiency

– Chronicity of thrombocytosis helpful

• Primary thrombocytosis

– Essential thrombocythemia

– (masked) polycythemia vera

– Need to exclude CML (BCR-ABL)

Essential ThrombocythemiaClinical Features

• Chronic thrombocytosis (often extreme, > 1 x 106/µL)

• Many patients are asymptomatic

• Vasomotor symptoms: headaches, syncope, visual disturbances, atypical chest pain, erythromelalgia (typically ASA-responsive)

• Thrombosis major cause of morbidity and mortality

– Both arterial and venous; unusual sites

– No clear association with platelet count

• Paradoxical increase in bleeding complications

– Risk factors/associations:• Extreme thrombocytosis > 1 million (controversial)• Use of ASA > 325 mg/day or other NSAIDs• Acquired VWD

• Splenomegaly

Essential ThrombocythemiaDiagnostic Criteria

• Platelet count ≥ 450,000

• JAK2 V617F+ OR no evidence of reactive thrombocytosis

• Not meeting WHO criteria for other MPNs (e.g PV, CML)

• Megakaryocyte proliferation with large and mature morphology; no or little granulocyte or erythroid proliferation

- ALL FOUR CRITERIA ARE “REQUIRED”

Essential Thrombocythemia

Bone marrow: Hypercellularity with marked megakaryocytic hyperplasia

Essential ThrombocythemiaCourse and Treatment

• Survival curves near age-matched controls

– Thrombosis major cause of morbidity and mortality

– Progression to myelofibrosis in ~5% and AML in ~1-5%

• Low dose aspirin indicated for all patients without history of bleeding

• Myelosuppresive therapy for high-risk patients (age > 60 OR h/o thrombosis)

– Hydroxyurea, anagrelide

• Treatment based on platelet count alone is controversial

• A 57 year-old man presents with fatigue, anorexia, and night sweats

• He also complains of abdominal discomfort and early satiety

• CBC reveals pancytopenia with an abnormal peripheral smear

Seg 35, bands 20, metamyelocytes 10, myelocytes 8, promyelocytes 4, blasts 3, teardrop RBCs, nRBCs

Primary MyelofibrosisDifferential Diagnosis

• Reactive myelofibrosis– Marrow infiltration with cancer – Infections (mycobacterial or fungus)– Myelodysplasia

• Other MPNs• Work-up

– Bone marrow biopsy– Genetic testing for JAK2 V617F and BCR-ABL

Primary myelofibrosis – clinical features

• Severe fatigue, weight loss, fevers, night sweats

• Splenomegaly, often massive

– LUQ discomfort/pain, early satiety

• Hepatomegaly

– Portal HTN related to HSMG – ascites, varices, UGIB

– Portal vein thrombosis

• Extramedullary hematopoiesis

– Foci can occur in almost any organ

• Cytopenias (but can also have leukocytosis, thrombocytosis)

• Leukoerythroblastic reaction

Leukoerythroblastic Reaction

Triad:• Tear drop RBC• Nucleated RBC• Immature myeloid cells

Associated with marrow infiltration

• Myelofibrosis• Cancer• Certain infections

Primary Myelofibrosis: Diagnostic Criteria

Primary Myelofibrosis

Bone marrow: Megakaryocytic hyperplasia with marked fibrosis

Primary MyelofibrosisCourse and Prognosis

• Median survival of only 3 years• Bone marrow failure

– Progressive cytopenias– RBC transfusion dependence– Susceptibility to infections– Hemorrhage

• Evolution to AML

Primary MyelofibrosisCourse and Prognosis

DIPSS:• Age >65 years: 1 point• Leukocyte count >25,000/microL: 1 point• Hemoglobin <10 g/dL: 2 points• Circulating blast cells ≥1 percent: 1 point• Presence of constitutional symptoms: 1 point

DIPSS category Points DIPSS-plus points

DIPSS-plus category

Low-risk 0 0 0

Intermediate-1 1-2 1 1

Intermediate-2 3-4 2 2-3

High-risk 5-6 3 4-6

Unfavorable karyotype 1

Platelets < 10,000/microL 1

RBC transfusion-dependence 1

Primary MyelofibrosisCourse and Prognosis

Primary myelofibrosis – treatment

• Supportive care– Transfusions– ESAs – not generally effective in PMF

• Hydroxyurea– Can be effective in controlling leukocytosis and/or thrombocytosis– Can ameliorate splenomegaly– Myelosuppression Is limiting factor

• Splenectomy– Indicated for severe symptoms related to SMG– May be helpful for improving anemia and/or thrombocytopenia

• Splenic irradiation– Considered for poor surgical candidates– Benefits are transient (3-6 months)

• BMT– Not an option for many patients

Primary myelofibrosis – treatment

• Well tolerated – initial study with higher doses of thalidomide poorly tolerated• 28% with ongoing response

– Durable treatment response for anemia and thrombocytopenia, not SMG

JAK2 inhibitors in MPNs

Anemia response by IWG

INCB018424 8%

TG101348 0%

CYT387 50%

Grade 3/4 thrombocytopenia

Grade 3/4anemia

INCB018424 20% 23%

TG101348 24% 35%

CYT387 27% 7%